A unique long acting anticoagulant

In 2004, ThromboGenics entered into a strategic collaborative research and licensing agreement with BioInvent to co-develop ThromboGenics’ novel antibody-based drugs. Currently, the partners are jointly developing TB-402 (anti-Factor VIII) and TB- 403 (anti-PlGF).

TB-402 is a novel human antibody binding to Factor VIII, an essential blood clotting factor. TB-402 is being developed as an anti-coagulant for the treatment and prevention of venous thromboembolic disorders such as deep vein thrombosis and atrial fibrillation. For the former the US has put out a call for action.

In 2007, ThromboGenics has successfully completed a Phase I clinical trial with TB-402. The study TB-402-001 was a randomized, placebo-controlled, dose escalation trial in healthy male volunteers, and the objective was to investigate safety, tolerability and pharmacokinetic properties of the drug candidate. 56 volunteers were enrolled into the trial, both young and old. Preliminary results of the trial showed that TB-402 met both the primary (safety and tolerability) and secondary (pharmacokinetic and pharmacodynamic) endpoints. The drug was well tolerated and the study showed that TB-402’s prolonged half-life may allow for single-dose treatment in orthopedic surgery patients and/or once a month administration for long-term stroke prevention in atrial fibrillation as opposed to current daily treatment. Importantly, the findings confirm that TB-402 achieves only partial inhibition of Factor VIII activity without the undesired effect of increased bleeding tendency in the case of total Factor VIII inactivation nor the need for regular monitoring of blood coagulation.

Two Phase I interaction studies have been completed as well. In the TB-402-002 study the effect of rhFVIII administration on coagulation parameters in healthy male volunteers treated with a single dose of TB- 402 was studied. The results of TB-402-002 support the strategy to counteract the anticoagulant activity of TB-402 with administration of rhFVIII.
In TB-402-003, the pharmacodynamic interactions between TB-402 and warfarin, and between TB-402 and LMWH (enoxaparin), were evaluated. This study demonstrated that administration of TB-402 to patients on warfarin with an INR between 2 and 3, and administration of LMWH (enoxaparin 1 mg/kg) to patients 48 hours after TB-402 administration, was safe. The results of this study support the recommendation to apply standard of care in case of documented venous thrombo-embolism in patients treated with TB-402.

The overall outcome of these three Phase I trials confirm the potential of TB-402 to provide a stable and long-acting anticoagulant effect after a single administration. These results were presented by Professor Peter Verhamme from the University of Leuven at the XXII Congress of the International Society on Thrombosis and Haemostasis (ISTH) on July 15, 2009 in Boston. ISTH presentation »

Based on the encouraging safety and pharmacodynamic results, the program has proceeded into Phase II clinical development. The first Phase II trial has evaluated single intravenous administration of TB-402 for the prophylaxis of venous thromboembolic events (VTE) after total knee replacement surgery. The study was a Phase II, dose-escalating, multicenter, prospective, randomised, active-controlled open label trial to investigate the safety and efficacy of three different dose regimens of TB-402 administered as a single bolus 18-24 hours post knee replacement surgery, compared with standard LMWH prophylaxis. The study has recruited 316 patients in different European countries.

For the pooled TB-402 treated group, 47 out of 218 (or 22%) patients experienced VTE; for the enoxaparin treated group, 30 out of 77 (or 39%) patients experienced VTE (p<0.05). The difference of reduction between the two groups is statistically significant.The study also showed that TB-402 and enoxaparin had a similar safety profile. The results of this trial (“Single intravenous administration of TB-402 for the prophylaxis of VTE after total knee replacement surgery”) will be presented by Prof. Peter Verhamme (University of Leuven, Belgium) at the 21st International Congress on Thrombosis in July in Milan, Italy.